ABSTRACT This K99/R00 application supports additional research training in computational mathematics and computer vision which will enable Dr. Madhusudhanan Balasubramanian-the applicant, to become an independent multidisciplinary investigator in computational ophthalmology. Specifically, in the K99 training phase of this grant, Dr. Balasubramanian will train at UC San Diego under the direction of Linda Zangwill PhD, an established glaucoma clinical researcher in the Department of Ophthalmology, as well as a team of co- mentors, including, Dr. Michael Holst from the Department of Mathematics and co-director for the Center for Computational Mathematics, and co-director of the Comptutational Science, Mathematics and Engineering and Dr. David Kriegman from Computer Science and Engineering. Training will be conducted via formal coursework, hands-on lab training, mentored research, progress review by an advisory committee, visiting collaborating researchers and regular attendance at seminars and workshops. The subsequent R00 independent research phase involves applying Dr. Balasubramanian's newly acquired computational techniques to the difficult task of identifying glaucomatous change over time from optical images of the optic nerve head and retinal nerve fiber layer. A documented presence of progressive optic neuropathy is the best gold standard currently available for glaucoma diagnosis. Confocal Scanning Laser Ophthalmoscope (CSLO) and Spectral Domain Optical Coherence Tomography (SD-OCT) are two of the optical imaging instruments available for monitoring the optic nerve head health in glaucoma diagnosis and management. Currently, several statistical and computational techniques are available for detecting localized glaucomatous changes from the CSLO exams. SD-OCT is a new generation ophthalmic imaging instrument based on the principle of optical interferometry. In contrast to the CSLO technology, SDOCT can resolve retinal layers from the internal limiting membrane (ILM) through the Bruch's membrane and can capture the 3-D architecture of the optic nerve head at a very high resolution. These high-resolution, high-dimensional volume scans introduce a new level of data complexity not seen in glaucoma progression analysis before and therefore, powerful (high-performance) computational techniques are required to fully utilize the high precision retinal measurements for glaucoma diagnosis. The central focus of this application in the K99 mentored phase of the application will be in 1) developing computational and statistical techniques for detecting structural glaucomatous changes in various retinal layers from the SDOCT scans, and 2) developing a new avenue of research in glaucoma management where in strain in retinal layers will be estimated non-invasively to characterize glaucomatous progression. In the R00 independent phase, the specific aims focus on developing 1) statistical and computational techniques for detecting volumetric glaucomatous change over time using 3-D SD-OCT volume scans and 2) a computational framework to estimate full-field 3-D volumetric strain from the standard SD-OCT scans.